Clinical heterogeneity of α-synuclein gene duplication in Parkinson's disease

Objective: Recently, genomic multiplications of (X-synuclein gene (SNCA) have been reported to cause hereditary early-onset parkinsonism. The objective of this study was to assess the frequency of SNCA multiplications among autosomal dominant hereditary Parkinson's disease (ADPD). Methods: We screened 113 ADPD probands and 200 sporadic PD cases by quantitative polymerase chain reaction and confirmed SNCA multiplications by flurorescence in situ hybridization (FISH) and comparative genomic hybridization array. Results: Two families (two patients from Family A and one from Family B) with SNCA duplication were identified among ADPD patients. Even though they had the same SNC4 duplication, one patient had dementia. Because there was exactly the same difference between the regions originated from each patient, the finding suggests that the phenotype of SNC4 multiplication may be also influenced by the range of duplication region. We also detected asymptomatic carriers in the families of both patients. Interestingly, the penetrance ratio was 33.3% (2/6) in one kindred, indicating that the ratio was very much lower than expected. Interpretation These two newly identified Japanese patients with SNC4 duplication and the five previously identified American and European families with SNCA triplication or duplication mutations indicate that the incidence of SNCA multiplication may be more frequent than previously estimated.